The primary function of the arterial chemoreceptors, i.e., the carotid and aortic bodies, is to transduce changes in arterial PO2, PCO2 and/or H+ ions, and possibly changes in temperature and osmolarity into nerve signals. There is no general agreement on how these physiological stimuli are changed into nerve impulses, nor is it known whether all stimuli act through a common mechanism. It is generally believed that one or more neuroactive substance(s) are involved in the transduction process. The long-term goal of the proposal is to evaluate the importance of the neuropeptide substance P (SP) in the process of chemoreception of the arterial chemoreceptors. It originates from data by ourselves and others showing that substance P and other related tachykinins stimulate the carotid body, and that substance P antagonists block the carotid body response to hypoxia. This project addresses the following issues: 1) Does substance P act similarly in the carotid and aortic bodies; 2) does it have the same effect in different species; and 3) how does it interact with other peptides found in the carotid body, such as vasoactive intestinal polypeptide and enkephalins, as well as with the known neurotransmitters like acetycholine, dopamine and norepinephrine. In addition, a major objective of the proposal is to determine where Substance P is localized in the carotid body and whether it is released by hypoxia and/or hypercapnia. In order to achieve the proposed goals, experiments will be carried out in anesthetized cats and rabbits. The general methods that will be employed are 1) neural recording of the in vivo and in vitro chemoreceptor discharge using single or paucifiber recording techniques; 2) immunocytochemical methods for histochemical localization of peptides in the chemoreceptors, and 3) biochemical techniques for characterizing the chemical nature and quantitative estimation for the release of peptides from the carotid bodies. These studies examine the basic transduction mechanisms of the carotid and aortic bodies. It could provide clues as to the transduction process at other visceral sensory receptors and may aid in the understanding of the role of peptides in the nervous system as well as other tissues. This proposal may also yield information of potential use in the treatment of hypoxemia and hypercarbia which are major problems in chronic obstructive lung diseases.